Wirkung von anti-diabetischen TZDs auf die Apoptose von CD4+-positiven Lymphozyten in atherosklerotischen Plaques
Auch gedruckt in der BibliothekZ: J-H 13.966; W: W-H 12.432
FakultätFakultät für Naturwissenschaften
Ressourcen- / MedientypDissertation, Text
Datum der Freischaltung2011-02-15
A previous clinical trial showed that four weeks treatment with the PPARgamma- activating anti-diabetic drug rosiglitazone decreased the content of CD4+-lymphocytes in atherosclerotic plaques of non-diabetic patients. The present study examined the underlying mechanisms which lead to a reduction of CD4+-lymphocytes under rosiglitazone-therapy. Immunohistochemical analysis of plaque-sections revealed that rosiglitazone-treated patients did not show differences in the expression of the chemokines RANTES, I-TAC, Mig and IP-10 compared to placebo. However, rosiglitazone treatment lead to an increased TUNEL- positivity of CD4+-lymphocytes in these patients. Stimulation of CD4+-lymphocytes with rosiglitazone increased the induction of apoptosis showed by Annexin V binding. Similar results were obtained for the non-glitazone and PPARgamma-activator GW1929, whereas pioglitazone a PPARalpha/gamma-activator showed only a weak effect on apoptosis induction. The PPARalpha-activators fenofibrate and WY14643 had no effect on lymphocyte apoptosis. Moreover pre-stimulation of CD4+-lymphocytes with these substances abolished rosiglitazone’s and camptothecin’s effect on apoptosis. Western-Blot-analysis showed that the expression of the pro-apoptotic proteins Bax and Bad is increased after stimulation of CD4+-lymphocytes with rosiglitazone whereas the expression of the anti-apoptotic protein Bcl-2 decreased. The second part of this study refers to the influence of telmisartan on CD4+-lymphocyte’s migration. Telmisartan is an angiotensin II type 1 receptor-blocker with PPARgamma-activating properties. The present study examined the effect of telmisartan on CD4+-lymphocyte’s migration and the role of PPARgamma in this context. Data of this work show that PPARgamma was successfully silenced in CD4+-lymphocytes by siRNA-transfection. Following ICAM3- assays revealed that telmisartan exhibits its anti-inflammatory actions on CD+-lymphocyte’s migration via the involvement of PPARgamma independent of the AT1R.
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